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Egr 1, a zinc finger transcription factor, shown to be important for B lymphoma growth was also down regulated on SFK inhibition. In typical B cells, Lyn is only transiently activated in response to BCR engagement by antigen. Singh et al showed that BCR engagement led to a Ca2 dependent, rapid manufacturing of reactive oxygen species, in particular H2O2.

The ROS in turn led to a fast and transient inhibition of protein tyrosine phosphatase activity related with the BCR due to the oxidation of the critical cysteine in the energetic site of PTP and a transient enhance in Lyn kinase activity. Hence the extent of PTP oxidation determines the activation status of Lyn. In the light of BYL719 this observation, and the data indicating a powerful correlation among ROS and lymphomagenesis, it is conceivable that B lymphoma cells have a larger level of production of ROS than the normal B cells and the large level of ROS right inactivates the PTPs, which causes phosphorylation and constitutive activation of Factor Xa . In help of this, we observed a greater level of global tyrosine phosphorylation in B lymphoma cells compared to the typical B cells.

It is fascinating to note that phosphorylation on Tyr507 of Lyn did not maintain Lyn inactive and Lyn is still phosphorylated on Tyr396. It could be that above expression of Lyn kinase promotes their aggregation and prospects to autophosphorylation on Tyr396 initial and an inactivation antigen peptide of SHP 1 by ROS keeps this phosphorylation steady. After Lyn is phosphorylated on Tyr396, it may be less affected by the phosphorylation on Tyr507 due to an inactivation of CD45. The complexity of the part of Lyn in B cells versus B lymphomas is reminiscent of its adverse role in regular myeloid cell development and its beneficial role for the growth of persistent myeloid leukemia cells, where Lyn inhibitors are already currently being tested in clinic. Similarly acute myeloid leukemia cells express constitutively energetic Lyn and their development is inhibited by PP2.

All round, our scientific studies recommend a model in which constitutive Lyn kinase activity phosphorylates Igand Igto mediate the constitutive BCR signaling for B lymphoma survival and growth. Our data also suggest that like other kinds of cancers, B lymphomas are heterogeneous. In addition to getting the constitutively energetic Lyn activity and constitutive BCR signaling, some lymphomas could have above expression of Bcl 2 anti apoptotic proteins due to chromosomal translocation of BCL2 gene into the Ig loci. For individuals B lymphomas with Bcl 2 expression, small Src kinase inhibitors such as dasatinib in combination with Bcl 2 inhibitors this kind of as ABT 737 could be a lot more productive than any single therapy.

BCR: B cell surface receptor, CML: persistent myelogenous leukemia, Csk: C terminal kinase, DLBCL: Diffuse LY364947 large Bcell lymphoma, ITAM: immunoreceptor tyrosine primarily based activation motifs, ITIM: immunoreceptor tyrosine based mostly inhibition motifs, NHL: Non Hodgkin lymphoma, PBLs: human peripheral blood lymphocytes, PI: propidium iodide, PKC: Protein Kinase C, PTP: protein tyrosine phosphatase, ROS: reactive oxygen species, SFK: Src Loved ones Protein Tyrosine Kinase.